Target Information
| Target General Information | Top | |||||
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| Target ID |
T36806
(Former ID: TTDR00732)
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| Target Name |
Kidney-type arginase (ARG2)
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| Synonyms |
Non-hepatic arginase; Human penile arginase; Arginase II; ARG2
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| Gene Name |
ARG2
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| Target Type |
Clinical trial target
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[1] | ||||
| Function |
May play a role in the regulation of extra-urea cycle arginine metabolism and also in down-regulation of nitric oxide synthesis. Extrahepatic arginase functions to regulate L-arginine bioavailability to NO synthase. Since NO synthase is found in the penile corpus cavernosum smooth muscle, the clitoral corpus cavernosum and the vagina, arginase II plays a role in both male and female sexual arousal. It is therefore a potential target for the treatment of male and female sexual arousal disorders.
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| BioChemical Class |
Carbon-nitrogen hydrolase
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| UniProt ID | ||||||
| EC Number |
EC 3.5.3.1
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| Sequence |
MSLRGSLSRLLQTRVHSILKKSVHSVAVIGAPFSQGQKRKGVEHGPAAIREAGLMKRLSS
LGCHLKDFGDLSFTPVPKDDLYNNLIVNPRSVGLANQELAEVVSRAVSDGYSCVTLGGDH SLAIGTISGHARHCPDLCVVWVDAHADINTPLTTSSGNLHGQPVSFLLRELQDKVPQLPG FSWIKPCISSASIVYIGLRDVDPPEHFILKNYDIQYFSMRDIDRLGIQKVMERTFDLLIG KRQRPIHLSFDIDAFDPTLAPATGTPVVGGLTYREGMYIAEEIHNTGLLSALDLVEVNPQ LATSEEEAKTTANLAVDVIASSFGQTREGGHIVYDQLPTPSSPDESENQARVRI Click to Show/Hide
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| HIT2.0 ID | T70MSG | |||||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Benzamidine | Ligand Info | |||||
| Structure Description | Crystal structure of human Arginase-2 complexed with inhibitor 9 | PDB:4HZE | ||||
| Method | X-ray diffraction | Resolution | 1.60 Å | Mutation | No | [4] |
| PDB Sequence |
HSVAVIGAPF
33 SQGQKRKGVE43 HGPAAIREAG53 LMKRLSSLGC63 HLKDFGDLSF73 TPVPKDDLYN 83 NLIVNPRSVG93 LANQELAEVV103 SRAVSDGYSC113 VTLGGDHSLA123 IGTISGHARH 133 CPDLCVVWVD143 AHADINTPLT153 TSSGNLHGQP163 VSFLLRELQD173 KVPQLPGFSW 183 IKPCISSASI193 VYIGLRDVDP203 PEHFILKNYD213 IQYFSMRDID223 RLGIQKVMER 233 TFDLLIGKRQ243 RPIHLSFDID253 AFDPTLAPAT263 GTPVVGGLTY273 REGMYIAEEI 283 HNTGLLSALD293 LVEVNPQLAT303 SEEEAKTTAN313 LAVDVIASSF323 GQTREG |
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: S-(2-boronoethyl)-L-cysteine | Ligand Info | |||||
| Structure Description | Human Arginase II: Crystal Structure and Physiological Role in Male and Female Sexual Arousal | PDB:1PQ3 | ||||
| Method | X-ray diffraction | Resolution | 2.70 Å | Mutation | No | [5] |
| PDB Sequence |
HSVAVIGAPF
33 SQGQKRKGVE43 HGPAAIREAG53 LMKRLSSLGC63 HLKDFGDLSF73 TPVPKDDLYN 83 NLIVNPRSVG93 LANQELAEVV103 SRAVSDGYSC113 VTLGGDHSLA123 IGTISGHARH 133 CPDLCVVWVD143 AHADINTPLT153 TSSGNLHGQP163 VSFLLRELQD173 KVPQLPGFSW 183 IKPCISSASI193 VYIGLRDVDP203 PEHFILKNYD213 IQYFSMRDID223 RLGIQKVMER 233 TFDLLIGKRQ243 RPIHLSFDID253 AFDPTLAPAT263 GTPVVGGLTY273 REGMYIAEEI 283 HNTGLLSALD293 LVEVNPQLAT303 SEEEAKTTAN313 LAVDVIASSF323 GQTREG |
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Arginine biosynthesis | hsa00220 | Affiliated Target |
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| Class: Metabolism => Amino acid metabolism | Pathway Hierarchy | ||
| Arginine and proline metabolism | hsa00330 | Affiliated Target |
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| Class: Metabolism => Amino acid metabolism | Pathway Hierarchy | ||
| Degree | 8 | Degree centrality | 8.59E-04 | Betweenness centrality | 1.19E-03 |
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| Closeness centrality | 2.06E-01 | Radiality | 1.36E+01 | Clustering coefficient | 1.43E-01 |
| Neighborhood connectivity | 1.05E+01 | Topological coefficient | 1.95E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 5 KEGG Pathways | + | ||||
| 1 | Arginine and proline metabolism | |||||
| 2 | Metabolic pathways | |||||
| 3 | Biosynthesis of antibiotics | |||||
| 4 | Biosynthesis of amino acids | |||||
| 5 | Amoebiasis | |||||
| NetPath Pathway | [+] 1 NetPath Pathways | + | ||||
| 1 | TCR Signaling Pathway | |||||
| WikiPathways | [+] 2 WikiPathways | + | ||||
| 1 | Urea cycle and metabolism of amino groups | |||||
| 2 | Metabolism of amino acids and derivatives | |||||
| References | Top | |||||
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| REF 1 | Arginase reciprocally regulates nitric oxide synthase activity and contributes to endothelial dysfunction in aging blood vessels. Circulation. 2003 Oct 21;108(16):2000-6. | |||||
| REF 2 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
| REF 3 | Probing erectile function: S-(2-boronoethyl)-L-cysteine binds to arginase as a transition state analogue and enhances smooth muscle relaxation in human penile corpus cavernosum. Biochemistry. 2001 Mar 6;40(9):2678-88. | |||||
| REF 4 | Discovery of (R)-2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid and congeners as highly potent inhibitors of human arginases I and II for treatment of myocardial reperfusion injury. J Med Chem. 2013 Mar 28;56(6):2568-80. | |||||
| REF 5 | Human arginase II: crystal structure and physiological role in male and female sexual arousal. Biochemistry. 2003 Jul 22;42(28):8445-51. | |||||
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